Homologous recombination deficiency (HRD) describes a condition where a cell’s specialized DNA repair system is impaired. Specifically, a highly accurate repair tool within this system is not functioning correctly. This impairment can have significant implications for cellular health and stability.
The Role of Homologous Recombination in DNA Repair
DNA within our cells is continuously subjected to various forms of damage, from environmental factors to normal cellular processes. To maintain its integrity, cells possess multiple pathways designed to detect and repair these lesions. Among these, homologous recombination (HR) is a high-fidelity system specifically tasked with repairing severe DNA damage known as “double-strand breaks” (DSBs). These breaks involve both strands of the DNA helix, posing a significant threat to genetic information.
The HR pathway utilizes an undamaged, identical copy of the DNA, typically a sister chromatid, as a precise template to guide the repair process. This ensures that the broken DNA strands are mended with exact accuracy, preventing errors or loss of genetic material. HR activity is most prominent during the S and G2 phases of the cell cycle, when sister chromatids are readily available to serve as templates. When the cell cannot rely on HR, it must resort to alternative, often more error-prone repair pathways. This reliance on less precise methods can lead to the accumulation of mutations and large-scale chromosomal alterations, disrupting the cell’s genetic stability.
Connection to Cancer Development
The accumulation of mutations and chromosomal changes resulting from faulty DNA repair, particularly due to homologous recombination deficiency, can lead to genomic instability. This instability means the cell’s genetic blueprint becomes highly disorganized and prone to further errors. Such extensive damage within the DNA can drive uncontrolled cell growth, a defining characteristic of cancer.
When cells lose their ability to accurately repair DNA double-strand breaks, they are more likely to acquire additional mutations that promote cancerous transformation. HRD has been observed in a range of human cancers, including ovarian, breast, prostate, and pancreatic cancers. Other cancer types, such as endometrial and bladder cancers, also show a prevalence of HRD.
Identifying Homologous Recombination Deficiency
Determining a tumor’s homologous recombination deficiency status is an important step in guiding treatment decisions. This status is primarily identified through specific tests performed on a sample of the tumor tissue. These diagnostic methods aim to uncover the underlying genetic alterations or the resulting genomic “scars” that indicate HRD.
One primary approach involves genetic testing to look for mutations in genes that are responsible for the HR pathway. The most well-known of these genes are BRCA1 and BRCA2, which play significant roles in accurate DNA repair. These mutations can be inherited (germline mutations) or arise spontaneously within tumor cells (somatic mutations).
Another method for identifying HRD is genomic instability testing, which assesses the overall pattern of DNA damage within the tumor. This type of testing looks for characteristic “scars” in the tumor’s DNA that are hallmarks of a defective HR pathway. Examples of these genomic signatures include loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST). These patterns reflect the cell’s struggle to repair its DNA without the high-fidelity HR system.
Therapeutic Implications and Targeted Treatments
The presence of homologous recombination deficiency, while contributing to cancer development, also creates a unique vulnerability in cancer cells that can be targeted with certain therapies. This vulnerability arises because HRD cells are heavily reliant on alternative DNA repair pathways to survive. Exploiting this reliance is a core principle behind targeted treatments for HRD-positive cancers.
Poly(ADP-ribose) polymerase (PARP) inhibitors are a primary class of targeted therapies that leverage this vulnerability. Their effectiveness is based on “synthetic lethality,” where the simultaneous impairment of two separate pathways leads to cell death, even though blocking either pathway alone might not. In a normal cell, both the HR pathway and the PARP-managed pathway contribute to DNA repair, allowing the cell to survive if one pathway is compromised.
PARP enzymes are normally involved in repairing single-strand breaks in DNA. When PARP inhibitors block this function, unrepaired single-strand breaks can accumulate and eventually lead to more severe double-strand breaks, especially during DNA replication. Cancer cells with homologous recombination deficiency already have a broken HR pathway, meaning they cannot effectively repair these newly formed double-strand breaks. Consequently, the combined failure of both the HR and PARP-managed repair systems results in catastrophic DNA damage and selective death of the cancer cell. This creates a therapeutic window where cancer cells are killed while normal, HR-proficient cells are largely spared. Beyond PARP inhibitors, tumors with HRD have also shown increased sensitivity to platinum-based chemotherapy agents. These agents induce DNA damage, including double-strand breaks, which HRD-positive cells are less equipped to repair, leading to greater efficacy.